Radical acylation of L-lysine derivatives and L-lysine-containing peptides by peroxynitrite-treated diacetyl and methylglyoxal

Radical acylation of L-lysine derivatives and L-lysine-containing peptides by peroxynitrite-treated diacetyl and methylglyoxal

Author Tokikawa, R. Google Scholar
Loffredo, C. Google Scholar
Uemi, M. Autor UNIFESP Google Scholar
Machini, M. T. Google Scholar
Bechara, E. J. H. Autor UNIFESP Google Scholar
Institution Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Abstract Highly electrophilic alpha-dicarbonyls such as diacetyl, methylglyoxal, 3-deoxyglucosone, and 4,5- dioxovaleric acid have been characterized as secondary catabolites that can aggregate proteins and form DNA nucleobase adducts in several human maladies, including Alzheimer' s disease, rheumatoid arthritis, diabetes, sepsis, renal failure, and respiratory distress syndrome. in vitro, diacetyl and methylglyoxal have also been shown to rapidly add up the peroxynitrite anion ( k (2) similar to 10 (4) - 10 (5) M (- 1) s (- 1)), a potent biological nucleophile, oxidant and nitrosating agent, followed by carbon chain cleavage to carboxylic acids via acetyl radical intermediate that can modify amino acids. in this study, we used the amino acid derivatives Ac-Lys-OMe and Z-Lys-OMe and synthesized the tetrapeptides H-KALA-OH, Ac-KALA-OH, and H-K( Boc) ALA-OH to reveal the preferential Lys amino group targeted by acyl radical generated by the a - dicarbonyl/peroxynitrite system. the pH profiles of the reactions are belll-shaped, peaking at approximately 7.5; hence, they are close to the pKa values of ONOOH and of the catalytic H (2) PO4 (-) anion. RP-HPLC and ESI-MS analyses of reaction products confi rmed N-alpha-and N-epsilon-acetylation of Lys by diacetyl as well as acetylation and formylation by methylglyoxal, with preference for the a -amino group. These data suggest the possibility of radical acylation of proteins in epigenetic processes, where enzymatic acetylation of these biomolecules is a welldocumented event, recently reported to be as critical to the cell cycle as phosphorylation. Also noteworthy is the observed formylation of L-Lys containing peptides by methylglyoxal never reported to occur in amino acid residues of peptides and proteins.
Keywords diacetyl
acetyl radical
amino acid acetylation
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
INCT Redoxoma (National Institute of Science and Technology of Redox Processes in Biomedicine)
Grant number FAPESP: 2006/56530-4
FAPESP: 2008/11695-1
Date 2014-03-01
Published in Free Radical Research. London: Informa Healthcare, v. 48, n. 3, p. 357-370, 2014.
ISSN 1071-5762 (Sherpa/Romeo, impact factor)
Publisher Informa Healthcare
Extent 357-370
Origin http://dx.doi.org/10.3109/10715762.2013.871386
Access rights Closed access
Type Article
Web of Science ID WOS:000332671600011
URI http://repositorio.unifesp.br/handle/11600/37534

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